Effect of metformin versus placebo on metabolic factors in the MA.32 randomized breast cancer trial

Pamela J Goodwin; Ryan J O Dowling; Marguerite Ennis; Bingshu E Chen; Wendy R Parulekar; Lois E Shepherd; Margot J Burnell; Rachel Vander Meer; Andrea Molckovsky; Anagha Gurjal; Karen A Gelmon; Jennifer A Ligibel; Dawn L Hershman; Ingrid A Mayer; Timothy J Whelan; Timothy J Hobday; Priya Rastogi; Manuela Rabaglio-Poretti; Julie Lemieux; Alastair M Thompson; Daniel Rea; Vuk Stambolic

doi:10.1038/s41523-021-00275-z

Effect of metformin versus placebo on metabolic factors in the MA.32 randomized breast cancer trial

Pamela J Goodwin, Ryan J O Dowling, Marguerite Ennis, Bingshu E Chen, Wendy R Parulekar, Lois E Shepherd, Margot J Burnell, Rachel Vander Meer, Andrea Molckovsky, Anagha Gurjal, Karen A Gelmon, Jennifer A Ligibel, Dawn L Hershman, Ingrid A Mayer, Timothy J Whelan, Timothy J Hobday, Priya Rastogi, Manuela Rabaglio-Poretti, Julie Lemieux, Alastair M ThompsonDaniel Rea, Vuk Stambolic

Cancer Research UK Clinical Trials Unit

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Abstract

Metformin may exert anticancer effects through indirect (mediated by metabolic changes) or direct mechanisms. The goal was to examine metformin impact on metabolic factors in non-diabetic subjects and determine whether this impact varies by baseline BMI, insulin, and rs11212617 SNP in CCTG MA.32, a double-blind placebo-controlled randomized adjuvant breast cancer (BC) trial. 3649 subjects with T1-3, N0-3, M0 BC were randomized; pretreatment and 6-month on-treatment fasting plasma was centrally assayed for insulin, leptin, highly sensitive C-reactive protein (hsCRP). Glucose was measured locally and homeostasis model assessment (HOMA) calculated. Genomic DNA was analyzed for the rs11212617 SNP. Absolute and relative change of metabolic factors (metformin versus placebo) were compared using Wilcoxon rank and t-tests. Regression models were adjusted for baseline differences and assessed interactions with baseline BMI, insulin, and the SNP. Mean age was 52 years. The majority had T2/3, node positive, hormone receptor positive, HER2 negative BC treated with (neo)adjuvant chemotherapy and hormone therapy. Median baseline body mass index (BMI) was 27.4 kg/m² (metformin) and 27.3 kg/m² (placebo). Median weight change was -1.4 kg (metformin) vs +0.5 kg (placebo). Significant improvements were seen in all metabolic factors, with 6 month standardized ratios (metformin/placebo) of 0.85 (insulin), 0.83 (HOMA), 0.80 (leptin), and 0.84 (hsCRP), with no qualitative interactions with baseline BMI or insulin. Changes did not differ by rs11212617 allele. Metformin (vs placebo) led to significant improvements in weight and metabolic factors; these changes did not differ by rs11212617 allele status.

Original language	English
Article number	74
Number of pages	8
Journal	Breast Cancer
Volume	7
Issue number	1
Early online date	8 Jun 2021
DOIs	https://doi.org/10.1038/s41523-021-00275-z
Publication status	Published - Dec 2021

Bibliographical note

Funding Information:
This work was supported by the Canadian Cancer Society Research Institute (#021039); National Cancer Institute (US) (#CA077202, CA180868, CA180822); The Breast Cancer Research Foundation (New York); Canadian Breast Cancer Foundation – Ontario Region, Ontario Institute for Cancer Research (#10NOV-467); Canadian Institutes of Health Research (#162296); Apotex Canada (in kind donation of placebo and metformin); and Hold’em for Life Charity. The study sponsors had no role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication.

Publisher Copyright:
© 2021, The Author(s).

ASJC Scopus subject areas

Oncology
Radiology Nuclear Medicine and imaging
Pharmacology (medical)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Goodwin, P. J., Dowling, R. J. O., Ennis, M., Chen, B. E., Parulekar, W. R., Shepherd, L. E., Burnell, M. J., Vander Meer, R., Molckovsky, A., Gurjal, A., Gelmon, K. A., Ligibel, J. A., Hershman, D. L., Mayer, I. A., Whelan, T. J., Hobday, T. J., Rastogi, P., Rabaglio-Poretti, M., Lemieux, J., ... Stambolic, V. (2021). Effect of metformin versus placebo on metabolic factors in the MA.32 randomized breast cancer trial. Breast Cancer, 7(1), Article 74. https://doi.org/10.1038/s41523-021-00275-z

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title = "Effect of metformin versus placebo on metabolic factors in the MA.32 randomized breast cancer trial",

abstract = "Metformin may exert anticancer effects through indirect (mediated by metabolic changes) or direct mechanisms. The goal was to examine metformin impact on metabolic factors in non-diabetic subjects and determine whether this impact varies by baseline BMI, insulin, and rs11212617 SNP in CCTG MA.32, a double-blind placebo-controlled randomized adjuvant breast cancer (BC) trial. 3649 subjects with T1-3, N0-3, M0 BC were randomized; pretreatment and 6-month on-treatment fasting plasma was centrally assayed for insulin, leptin, highly sensitive C-reactive protein (hsCRP). Glucose was measured locally and homeostasis model assessment (HOMA) calculated. Genomic DNA was analyzed for the rs11212617 SNP. Absolute and relative change of metabolic factors (metformin versus placebo) were compared using Wilcoxon rank and t-tests. Regression models were adjusted for baseline differences and assessed interactions with baseline BMI, insulin, and the SNP. Mean age was 52 years. The majority had T2/3, node positive, hormone receptor positive, HER2 negative BC treated with (neo)adjuvant chemotherapy and hormone therapy. Median baseline body mass index (BMI) was 27.4 kg/m2 (metformin) and 27.3 kg/m2 (placebo). Median weight change was -1.4 kg (metformin) vs +0.5 kg (placebo). Significant improvements were seen in all metabolic factors, with 6 month standardized ratios (metformin/placebo) of 0.85 (insulin), 0.83 (HOMA), 0.80 (leptin), and 0.84 (hsCRP), with no qualitative interactions with baseline BMI or insulin. Changes did not differ by rs11212617 allele. Metformin (vs placebo) led to significant improvements in weight and metabolic factors; these changes did not differ by rs11212617 allele status.",

author = "Goodwin, {Pamela J} and Dowling, {Ryan J O} and Marguerite Ennis and Chen, {Bingshu E} and Parulekar, {Wendy R} and Shepherd, {Lois E} and Burnell, {Margot J} and {Vander Meer}, Rachel and Andrea Molckovsky and Anagha Gurjal and Gelmon, {Karen A} and Ligibel, {Jennifer A} and Hershman, {Dawn L} and Mayer, {Ingrid A} and Whelan, {Timothy J} and Hobday, {Timothy J} and Priya Rastogi and Manuela Rabaglio-Poretti and Julie Lemieux and Thompson, {Alastair M} and Daniel Rea and Vuk Stambolic",

note = "Funding Information: This work was supported by the Canadian Cancer Society Research Institute (#021039); National Cancer Institute (US) (#CA077202, CA180868, CA180822); The Breast Cancer Research Foundation (New York); Canadian Breast Cancer Foundation – Ontario Region, Ontario Institute for Cancer Research (#10NOV-467); Canadian Institutes of Health Research (#162296); Apotex Canada (in kind donation of placebo and metformin); and Hold{\textquoteright}em for Life Charity. The study sponsors had no role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

doi = "10.1038/s41523-021-00275-z",

language = "English",

volume = "7",

journal = "Breast Cancer",

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Goodwin, PJ, Dowling, RJO, Ennis, M, Chen, BE, Parulekar, WR, Shepherd, LE, Burnell, MJ, Vander Meer, R, Molckovsky, A, Gurjal, A, Gelmon, KA, Ligibel, JA, Hershman, DL, Mayer, IA, Whelan, TJ, Hobday, TJ, Rastogi, P, Rabaglio-Poretti, M, Lemieux, J, Thompson, AM, Rea, D & Stambolic, V 2021, 'Effect of metformin versus placebo on metabolic factors in the MA.32 randomized breast cancer trial', Breast Cancer, vol. 7, no. 1, 74. https://doi.org/10.1038/s41523-021-00275-z

TY - JOUR

T1 - Effect of metformin versus placebo on metabolic factors in the MA.32 randomized breast cancer trial

AU - Goodwin, Pamela J

AU - Dowling, Ryan J O

AU - Ennis, Marguerite

AU - Chen, Bingshu E

AU - Parulekar, Wendy R

AU - Shepherd, Lois E

AU - Burnell, Margot J

AU - Vander Meer, Rachel

AU - Molckovsky, Andrea

AU - Gurjal, Anagha

AU - Gelmon, Karen A

AU - Ligibel, Jennifer A

AU - Hershman, Dawn L

AU - Mayer, Ingrid A

AU - Whelan, Timothy J

AU - Hobday, Timothy J

AU - Rastogi, Priya

AU - Rabaglio-Poretti, Manuela

AU - Lemieux, Julie

AU - Thompson, Alastair M

AU - Rea, Daniel

AU - Stambolic, Vuk

N1 - Funding Information: This work was supported by the Canadian Cancer Society Research Institute (#021039); National Cancer Institute (US) (#CA077202, CA180868, CA180822); The Breast Cancer Research Foundation (New York); Canadian Breast Cancer Foundation – Ontario Region, Ontario Institute for Cancer Research (#10NOV-467); Canadian Institutes of Health Research (#162296); Apotex Canada (in kind donation of placebo and metformin); and Hold’em for Life Charity. The study sponsors had no role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication. Publisher Copyright: © 2021, The Author(s).

PY - 2021/12

Y1 - 2021/12

N2 - Metformin may exert anticancer effects through indirect (mediated by metabolic changes) or direct mechanisms. The goal was to examine metformin impact on metabolic factors in non-diabetic subjects and determine whether this impact varies by baseline BMI, insulin, and rs11212617 SNP in CCTG MA.32, a double-blind placebo-controlled randomized adjuvant breast cancer (BC) trial. 3649 subjects with T1-3, N0-3, M0 BC were randomized; pretreatment and 6-month on-treatment fasting plasma was centrally assayed for insulin, leptin, highly sensitive C-reactive protein (hsCRP). Glucose was measured locally and homeostasis model assessment (HOMA) calculated. Genomic DNA was analyzed for the rs11212617 SNP. Absolute and relative change of metabolic factors (metformin versus placebo) were compared using Wilcoxon rank and t-tests. Regression models were adjusted for baseline differences and assessed interactions with baseline BMI, insulin, and the SNP. Mean age was 52 years. The majority had T2/3, node positive, hormone receptor positive, HER2 negative BC treated with (neo)adjuvant chemotherapy and hormone therapy. Median baseline body mass index (BMI) was 27.4 kg/m2 (metformin) and 27.3 kg/m2 (placebo). Median weight change was -1.4 kg (metformin) vs +0.5 kg (placebo). Significant improvements were seen in all metabolic factors, with 6 month standardized ratios (metformin/placebo) of 0.85 (insulin), 0.83 (HOMA), 0.80 (leptin), and 0.84 (hsCRP), with no qualitative interactions with baseline BMI or insulin. Changes did not differ by rs11212617 allele. Metformin (vs placebo) led to significant improvements in weight and metabolic factors; these changes did not differ by rs11212617 allele status.

AB - Metformin may exert anticancer effects through indirect (mediated by metabolic changes) or direct mechanisms. The goal was to examine metformin impact on metabolic factors in non-diabetic subjects and determine whether this impact varies by baseline BMI, insulin, and rs11212617 SNP in CCTG MA.32, a double-blind placebo-controlled randomized adjuvant breast cancer (BC) trial. 3649 subjects with T1-3, N0-3, M0 BC were randomized; pretreatment and 6-month on-treatment fasting plasma was centrally assayed for insulin, leptin, highly sensitive C-reactive protein (hsCRP). Glucose was measured locally and homeostasis model assessment (HOMA) calculated. Genomic DNA was analyzed for the rs11212617 SNP. Absolute and relative change of metabolic factors (metformin versus placebo) were compared using Wilcoxon rank and t-tests. Regression models were adjusted for baseline differences and assessed interactions with baseline BMI, insulin, and the SNP. Mean age was 52 years. The majority had T2/3, node positive, hormone receptor positive, HER2 negative BC treated with (neo)adjuvant chemotherapy and hormone therapy. Median baseline body mass index (BMI) was 27.4 kg/m2 (metformin) and 27.3 kg/m2 (placebo). Median weight change was -1.4 kg (metformin) vs +0.5 kg (placebo). Significant improvements were seen in all metabolic factors, with 6 month standardized ratios (metformin/placebo) of 0.85 (insulin), 0.83 (HOMA), 0.80 (leptin), and 0.84 (hsCRP), with no qualitative interactions with baseline BMI or insulin. Changes did not differ by rs11212617 allele. Metformin (vs placebo) led to significant improvements in weight and metabolic factors; these changes did not differ by rs11212617 allele status.

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Effect of metformin versus placebo on metabolic factors in the MA.32 randomized breast cancer trial

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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